{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T16:13:10Z","timestamp":1783354390651,"version":"3.54.6"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005063","name":"Excellent Young Talents Fund Program of Higher Education Institutions of Anhui Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005063","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009004","name":"Anhui University of Chinese Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009004","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010814","name":"Anhui Provincial Department of Education","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010814","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>Pseudomonas aeruginosa<\/jats:italic> is a major nosocomial pathogen that frequently causes ventilator-associated pneumonia in specific populations. Sodium houttuyfonate (SH) has shown mild antibacterial activity against <jats:italic>P. aeruginosa in vitro<\/jats:italic>, but the mechanism of potent antimicrobial activity of SH against <jats:italic>P. aeruginosa<\/jats:italic> infection <jats:italic>in vivo<\/jats:italic> remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, using the mouse pneumonia model induced by <jats:italic>P. aeruginosa<\/jats:italic> nasal drip to explore the therapeutic effects of SH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that SH exhibits dose-dependent therapeutic effects of reducing <jats:italic>P. aeruginosa<\/jats:italic> burden and systemic inflammation in pneumonia mice. SH ameliorates inflammatory gene expression and production of inflammatory proteins, such as interleukin-6 (IL-6), nuclear factor kappa-B (NF-\u03baB) and toll-like receptor 4 (TLR4), associated with the TLR4\/NF-\u03baB pathway in mice with <jats:italic>P. aeruginosa<\/jats:italic> pneumonia. Furthermore, we analyzed the intestinal flora of mice and found that compared with the model group, the abundance and diversity of beneficial bacterial flora of SH treatment groups increased significantly, suggesting that SH can improve the intestinal flora disorder caused by inflammation. In addition, SH improves alpha and beta diversity index and reduces species abundance differences of intestinal flora in pneumonia mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Taken together, our presented results indicate that SH may effectively alleviate the acute pulmonary infection induced by <jats:italic>P. aeruginosa<\/jats:italic> by reducing the disturbance of regulating immunity and intestinal flora in mice.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2022.1022511","type":"journal-article","created":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T04:39:15Z","timestamp":1669869555000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Sodium houttuyfonate effectively treats acute pulmonary infection of Pseudomonas aeruginosa by affecting immunity and intestinal flora in mice"],"prefix":"10.3389","volume":"12","author":[{"given":"Tian","family":"Zhuang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengxue","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longfei","family":"Mei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changzhong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojia","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daqiang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1139\/cjpp-2013-0073","article-title":"Co-Administration of aqueous ginseng extract with tobramycin stimulates the pro-inflammatory response and promotes the killing of pseudomonas aeruginosa in the lungs of infected rats","volume":"91","author":"Alipour","year":"2013","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3998","DOI":"10.1128\/iai.68.7.3998-4004.2000","article-title":"Acquisition of expression of the pseudomonas aeruginosa ExoU cytotoxin leads to increased bacterial virulence in a murine model of acute pneumonia and systemic spread","volume":"68","author":"Allewelt","year":"2000","journal-title":"Infect. Immun."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1164\/rccm.201512-2424OC","article-title":"Airway microbiota determines innate cell inflammatory or tissue remodeling profiles in lung transplantation","volume":"194","author":"Bernasconi","year":"2016","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/5066434","article-title":"Qiguiyin decoction improves multidrug-resistant pseudomonas aeruginosa infection in rats by regulating inflammatory cytokines and the TLR4\/MyD88\/NF-\u03baB signaling pathway","volume":"2022","author":"Chen","year":"2022","journal-title":"BioMed. Res. Int."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.01187","article-title":"Astilbin inhibits high glucose-induced inflammation and extracellular matrix accumulation by suppressing the TLR4\/MyD88\/NF-\u03baB pathway in rat glomerular mesangial cells","volume":"9","author":"Chen","year":"2018","journal-title":"Front. Pharmacol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"56845","DOI":"10.3791\/56845","article-title":"Guided protocol for fecal microbial characterization by 16S rRNA-amplicon sequencing","volume":"2018","author":"Di Segni","year":"2018","journal-title":"J. Vis. Exp."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.4049\/jimmunol.1101682","article-title":"Transient TLR activation restores inflammatory response and ability to control pulmonary bacterial infection in germfree mice","volume":"188","author":"Fagundes","year":"2012","journal-title":"J. Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.phrs.2019.02.024","article-title":"Gut microbiota, a new frontier to understand traditional Chinese medicines","volume":"142","author":"Feng","year":"2019","journal-title":"Pharmacol. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1139\/y10-049","article-title":"Effect of sodium houttuyfonate on inhibiting ventricular remodeling induced by abdominal aortic banding in rats","volume":"88","author":"Gao","year":"2010","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"405","DOI":"10.5114\/aoms.2011.23403","article-title":"The protective effects of ambroxol in pseudomonas aeruginosa-induced pneumonia in rats","volume":"7","author":"Gao","year":"2011","journal-title":"Arch. Med. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1007\/s10096-013-1876-y","article-title":"Pseudomonas aeruginosa infection in cystic fibrosis lung disease and new perspectives of treatment: A review","volume":"32","author":"Gaspar","year":"2013","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"B12","doi-asserted-by":"publisher","first-page":"51320","DOI":"10.18632\/oncotarget.9710","article-title":"16S rRNA amplicon sequencing identifies microbiota associated with oral cancer, human papilloma virus infection and surgical treatment","volume":"7","author":"Guerrero-Preston","year":"2016","journal-title":"Oncotarget"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.3390\/nu11071613","article-title":"Gut microbiome: Profound implications for diet and disease","volume":"11","author":"Hills","year":"2019","journal-title":"Nutrients"},{"key":"B14","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.bmcl.2014.10.072","article-title":"Sodium houttuyfonate and EDTA-Na2 in combination effectively inhibits pseudomonas aeruginosa, staphylococcus aureus and candida albicans in vitro and in vivo","volume":"25","author":"Huang","year":"2015","journal-title":"Bioorg Med. Chem. Lett."},{"key":"B15","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/s13099-016-0149-6","article-title":"Impacts of resistant starch and wheat bran consumption on enteric inflammation in relation to colonic bacterial community structures and short-chain fatty acid concentrations in mice","volume":"8","author":"Jiminez","year":"2016","journal-title":"Gut Pathog."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1001\/jama.2021.13355","article-title":"Effect of probiotics on incident ventilator-associated pneumonia in critically ill patients: A randomized clinical trial","volume":"326","author":"Johnstone","year":"2021","journal-title":"Jama"},{"key":"B17","doi-asserted-by":"publisher","first-page":"5300","DOI":"10.1128\/iai.00501-09","article-title":"Inescapable need for neutrophils as mediators of cellular innate immunity to acute pseudomonas aeruginosa pneumonia","volume":"77","author":"Koh","year":"2009","journal-title":"Infect. Immun."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a001651","article-title":"The nuclear factor NF-kappaB pathway in inflammation","volume":"1","author":"Lawrence","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1038\/nature03491","article-title":"IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation","volume":"434","author":"Lawrence","year":"2005","journal-title":"Nature"},{"key":"B20","first-page":"24","article-title":"Effect of alleric contct dermatitis mice \u2018indexes of spleen, thymus, IFN-\u03b3 and IL-4s\u2019 change caused by shu feng yin","volume":"25","author":"Li","year":"2011","journal-title":"J. Pract. Tradit Chin. Intern. Med."},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.00454","article-title":"Multi-omics analysis reveals a correlation between the host phylogeny, gut microbiota and metabolite profiles in cyprinid fishes","volume":"8","author":"Li","year":"2017","journal-title":"Front. Microbiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.3892\/mmr.2014.2965","article-title":"Effect of melilotus extract on lung injury via the upregulation of tumor necrosis factor-\u03b1-induced protein-8-like 2 in septic mice","volume":"11","author":"Liu","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"B24","first-page":"1338","article-title":"A mouse model of mycoplasma pneumoniae pneumonia","author":"Liu","year":"2004","journal-title":"Chongqing Med."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2021.174110","article-title":"Sodium houttuyfonate: A review of its antimicrobial, anti-inflammatory and cardiovascular protective effects","volume":"902","author":"Liu","year":"2021","journal-title":"Eur. J. Pharmacol."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013027","article-title":"Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer","volume":"5","author":"Lowe","year":"2010","journal-title":"PloS One"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/srep26337","article-title":"Mucosal adherent bacterial dysbiosis in patients with colorectal adenomas","volume":"6","author":"Lu","year":"2016","journal-title":"Sci. Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1586\/17476348.2014.927736","article-title":"Immunomodulatory adjuvant therapy in severe community-acquired pneumonia","volume":"8","author":"Morton","year":"2014","journal-title":"Expert Rev. Respir. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1097\/shk.0000000000000796","article-title":"Fc gamma receptor IIB deficient mice: A lupus model with increased endotoxin tolerance-related sepsis susceptibility","volume":"47","author":"Ondee","year":"2017","journal-title":"Shock"},{"key":"B29","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.biotechadv.2018.11.013","article-title":"Antibiotic resistance in pseudomonas aeruginosa: Mechanisms and alternative therapeutic strategies","volume":"37","author":"Pang","year":"2019","journal-title":"Biotechnol. Adv."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00906","article-title":"The genus alistipes: Gut bacteria with emerging implications to inflammation, cancer, and mental health","volume":"11","author":"Parker","year":"2020","journal-title":"Front. Immunol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1830","DOI":"10.1007\/s10620-018-5428-2","article-title":"Gut microbiome, short-chain fatty acids, and mucosa injury in young adults with human immunodeficiency virus infection","volume":"64","author":"Qing","year":"2019","journal-title":"Dig Dis. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3429","DOI":"10.1073\/pnas.0500599102","article-title":"Synergistic proinflammatory responses induced by polymicrobial colonization of epithelial surfaces","volume":"102","author":"Ratner","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.110674","article-title":"Bacterial dysbiosis incites Th17 cell revolt in irradiated gut","volume":"131","author":"Shao","year":"2020","journal-title":"BioMed. Pharmacother."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.596492","article-title":"Sodium houttuyfonate inhibits bleomycin induced pulmonary fibrosis in mice","volume":"12","author":"Shen","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.jep.2018.03.038","article-title":"Therapeutic potentials of houttuynia cordata thunb. against inflammation and oxidative stress: A review","volume":"220","author":"Shingnaisui","year":"2018","journal-title":"J. Ethnopharmacol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1007\/s00438-016-1282-0","article-title":"Comparative analysis of the gut microbiota of black bears in China using high-throughput sequencing","volume":"292","author":"Song","year":"2017","journal-title":"Mol. Genet. Genomics"},{"key":"B38","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1016\/j.biopha.2018.07.014","article-title":"Role of TLR4\/MyD88\/NF-\u03baB signaling pathway in coronary microembolization-induced myocardial injury prevented and treated with nicorandil","volume":"106","author":"Su","year":"2018","journal-title":"BioMed. Pharmacother."},{"key":"B37","doi-asserted-by":"publisher","first-page":"3272","DOI":"10.4049\/jimmunol.178.5.3272","article-title":"Expression profile of FcgammaRIIb on leukocytes and its dysregulation in systemic lupus erythematosus","volume":"178","author":"Su","year":"2007","journal-title":"J. Immunol."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.107272","article-title":"Effect of gut microbiota on LPS-induced acute lung injury by regulating the TLR4\/NF-\u03baB signaling pathway","volume":"91","author":"Tang","year":"2021","journal-title":"Int. Immunopharmacol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.cbpb.2019.01.004","article-title":"Molecular cloning of IL-6, IL-10, IL-11, IFN-\u0264 and modulation of pro- and anti-inflammatory cytokines in cobia (Rachycentron canadum) after photobacterium damselae subsp. piscicida infection","volume":"230","author":"Tran","year":"2019","journal-title":"Comp. Biochem. Physiol. B Biochem. Mol. Biol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1007\/s11033-018-4497-9","article-title":"Sodium houttuyfonate in vitro inhibits biofilm dispersion and expression of bdlA in pseudomonas aeruginosa","volume":"46","author":"Wang","year":"2019","journal-title":"Mol. Biol. Rep."},{"key":"B43","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.micpath.2017.03.011","article-title":"Sodium houttuyfonate inhibits LPS-induced inflammatory response via suppressing TLR4\/NF-\u03baB signaling pathway in bovine mammary epithelial cells","volume":"107","author":"Wang","year":"2017","journal-title":"Microb. Pathog."},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/srep32002","article-title":"Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"B45","doi-asserted-by":"publisher","first-page":"753","DOI":"10.3892\/etm.2015.2562","article-title":"Sodium houttuyfonate inhibits biofilm formation and alginate biosynthesis-associated gene expression in a clinical strain of pseudomonas aeruginosa in vitro","volume":"10","author":"Wu","year":"2015","journal-title":"Exp. Ther. Med."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.714694","article-title":"Houttuynia cordata thunb: An ethnopharmacological review","volume":"12","author":"Wu","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2014.00635","article-title":"Sodium houttuyfonate affects production of n-acyl homoserine lactone and quorum sensing-regulated genes expression in pseudomonas aeruginosa","volume":"5","author":"Wu","year":"2014","journal-title":"Front. Microbiol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1164\/rccm.201202-0182OC","article-title":"Th17-stimulating protein vaccines confer protection against pseudomonas aeruginosa pneumonia","volume":"186","author":"Wu","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1007\/s10753-017-0650-1","article-title":"Effects of sodium houttuyfonate on pulmonary inflammation in COPD model rats","volume":"40","author":"Wu","year":"2017","journal-title":"Inflammation"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/1934578x20972518","article-title":"Sodium houttuyfonate and sodium new houttuyfonate affect the composition of gut microbiota and production of inflammatory factors in mice","volume":"15","author":"Yan","year":"2020","journal-title":"Natural Product Commun."},{"key":"B50","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1007\/s00430-016-0466-x","article-title":"Expression of inflammation-related genes in the lung of BALB\/c mice response to H7N9 influenza a virus with different pathogenicity","volume":"205","author":"Yu","year":"2016","journal-title":"Med. Microbiol. Immunol."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.107058","article-title":"Sodium houttuyfonate enhances the intestinal barrier and attenuates inflammation induced by salmonella typhimurium through the NF-\u03baB pathway in mice","volume":"89","author":"Zhang","year":"2020","journal-title":"Int. Immunopharmacol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.03020","article-title":"Predominant role of immunoglobulin G in the pathogenesis of splenomegaly in murine lupus","volume":"10","author":"Zhang","year":"2019","journal-title":"Front. Immunol."},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00575","article-title":"Intestinal flora and disease mutually shape the regional immune system in the intestinal tract","volume":"11","author":"Zhou","year":"2020","journal-title":"Front. Immunol."},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/srep22044","article-title":"Protective effects of fenofibrate against acute lung injury induced by intestinal ischemia\/reperfusion in mice","volume":"6","author":"Zhu","year":"2016","journal-title":"Sci. Rep."},{"key":"B55","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1111\/j.1365-2249.2005.02964.x","article-title":"Cellular immunity in healthy volunteers treated with an octavalent conjugate pseudomonas aeruginosa vaccine","volume":"143","author":"Zuercher","year":"2006","journal-title":"Clin. Exp. Immunol."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.1022511\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T04:39:20Z","timestamp":1669869560000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.1022511\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,1]]},"references-count":55,"alternative-id":["10.3389\/fcimb.2022.1022511"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.1022511","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,1]]},"article-number":"1022511"}}